Panayiotopoulos syndrome with convulsive status epilepticus at the onset: A long-term study

Panayiotopoulos syndrome with convulsive status epilepticus at the onset: A long-term studyPanayiotopoulos syndrome with convulsive status epilepticus at the onset: A long-term study
Alberto Verrotti a,*, Marianna Sebastiani b, Lucio Giordano c, Pasquale Striano d, Vincenzo Belcastro e, Emilio Franzoni f, Pasquale Parisi g, Dario Pruna h, Alberto Spalice i, Aglaia Vignoli j, Salvatore Grosso k
a Department of Pediatrics, University of Perugia, Perugia, Italy b Department of Pediatrics, University of Chieti, Chieti, Italy c Pediatric Neuropsychiatric Division, ‘‘Spedali Civili’’, Brescia, Italy d Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics,
Maternal and Child Health, Institute ‘‘Gaslini’’, University of Genova, Genova, Italy e Neurology Unit, Department of Neuroscience, ‘‘Sant’Anna’’ Hospital, Como, Italy f Neuropsychiatry Unit, Department of Pediatrics, University of Bologna, Bologna, Italy g Child Neurology, Chair of Pediatrics, II Faculty of Medicine, University of Rome, Rome, Italy h Epilepsy Unit, Child Neuropsychiatry Department, University Hospital, Cagliari, Italy i Division of Child Neurology, Department of Pediatrics, University ‘‘La Sapienza’’ Rome, Rome, Italy j Epilepsy Center, San Paolo Hospital, University of Milan, Milan, Italy k Department of Pediatrics, University of Siena, Siena, Italy
A R T I C L E I N F O
Article history:
Accepted 29 May 2014
A B S T R A C T
Purpose: To better define the convulsive status epilepticus (CSE) as a possible manifestation at the onset
of Panayiotopoulos syndrome (PS) and to assess its prognostic value in these children.
Methods: Children with CSE and diagnostic criteria of PS were identified, followed clinically and
compared with a group of patients with PS without CSE from 1993 to 2012.
Results: We identified 37 patients with CSE at the onset of PS. During the same period we identified 72
children with autonomic symptoms of PS without CSE. The first episode of CSE occurred at a mean age of
6.5 years. Generalized clonic seizures were the most common ictal event and one-third of the patients
required admission to Intensive Care Units. Interictal EEGs showed occipital spike activity in 31 (83.7%)
subjects. Only 14 (37.8%) patients were treated with valproic acid and for two of them (5.40%) it was
necessary to administer other drugs. There were no intractable cases. The overall prognosis was
excellent. After the first event, 15 subjects (40.54%) experienced at least another typical PS seizure, but
all patients were seizure free at the last follow-up.
Conclusion: CSE is not uncommon in PS and it may occur at the onset of benign childhood epilepsy,
without leading to a poor prognosis.
2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Contents lists available at ScienceDirect
Seizure
jou r nal h o mep age: w ww.els evier . co m/lo c ate /ys eiz
1. Introduction
Panayiotopoulos syndrome (PS) is a relatively common early- onset benign childhood epilepsy, with an estimated prevalence of around 13% of all epilepsies among 3–6 years-old children, with
* Corresponding author at: Department of Pediatrics, University of Perugia,
‘‘Santa Maria della Misericordia’’ Hospital, piazzale Menghini 1, 06156 Perugia,
Italy. Tel.: +39 075 5784417; fax: +39 075 5784417.
E-mail address: [email protected] (A. Verrotti).
http://dx.doi.org/10.1016/j.seizure.2014.05.013
1059-1311/ 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights re
one or more non-febrile seizures, and 6% in the age group between 1 and 15 years.1,2 In the late 80s, Panayiotopoulos first described the syndrome, defining the clinical triad of vomiting, tonic eye deviation and nocturnal seizures.3,4 Recently, PS was recognized by the ILAE5 and subsequently confirmed in independent prospective studies.4,6 PS is characterized by an unusual variety of autonomic symptoms and typical EEG findings. Generally, seizures start with autonomic signs (81%), mainly vomiting (72%), occurring during sleep (70%), alone or associated with behavioral changes, such as loss of consciousness.7 In half of the cases, seizures lasted more than 30 min, therefore leading to an autonomic status epilepticus,
served.
repetitive spike wave complexes over the left hemisphere.
A. Verrotti et al. / Seizure 23 (2014) 728–731 729
occasionally presenting with ictal vomiting, tachycardia, pallor, flushing or cyanosis and prolonged thermoregulatory changes, lasting for hours.2
The EEG of patients with PS shows great variability in terms of localization, but two-thirds of patients present a multifocal interictal EEG with predominant occipital spikes.6 EEG foci frequently shift and increase in number and localization. Thus, frontal or centro-temoporal spikes, generalized discharges alone or in combination may be present.1,8
The main features of PS are the autonomic seizures and occasionally these autonomic symptoms can present with a prominent impact on cardiac and respiratory functions. Mujawar et al.9 reported the case of a 3 year-old child with a diagnosis of PS who presented an ictal cardiorepiratory arrest requiring cardio- pulmunary resuscitation. However, this is an extremely rare event, with only 4 cases being reported in the literature.9
The incidence of sudden unexplained death in epilepsy (SUDEP) is estimated to be 0.35–1.8 per 1000 patient-years and the risk is significantly increased (about 3–9 per 1000 patient-years) in those with intractable epilepsy.10,11 The pathophysiology of this severe complication of epilepsy remains unclear; however, some ictal autonomic changes, particularly cardiac, respiratory and cerebral mechanisms, are probably involved in the etiology of SUDEP. These factors could directly influence the excitation of neocortical and limbic cortices and the responses of other structures, which represent the central autonomic network. Considering the above mentioned mechanisms, it is reasonable to think that patients with PS could present SUDEP as the worst complication. Based on to the prevalence of PS and SUDEP, we could assume that this devastating event might occur in about 1 out of 200 cases with PS.12
It seems that convulsive status epilepticus (CSE) is a rare event, mainly at the onset of PS. There are few data suggesting that CSE in PS is an exceptional event.13 Fejerman et al. reported two cases of SE with electroclinical features presenting in the context of benign partial epilepsies,14 while Ferrie et al. described a rolandic epilepsy followed by an autonomic status epilepticus in a patient with PS at the onset, defined as an atypical evolution.15
The aim of the present multicenter study was to analyze the electro-clinical features and long-term outcomes in a cohort of patients with CSE at the onset of PS. In order to assess the potential prognostic role of CSE at the onset, we compared the long-term evolution of these patients with a group of patients with PS but without CSE.
2. Patients and methods
A cohort of 37 patients with PS was selected in 8 neurological and general pediatric centers from 1993 to 2012. All patients were referred to these institutions for CSE without fever, considering status epilepticus an event characterized by 30 min of continuous seizure activity or at least two sequential seizures without full recovery of consciousness between seizures.16 According to the definition proposed by the Epilepsy Foundation of America (Epilepsy Foundation of America’s Working Group on Status Epilepticus, 1993),17 we considered the convulsive form of status epilepticus defined as the repeated generalized convulsive seizures with persistent postictal depression of neurological function between seizures or partial seizures manifested as focal motor convulsions. All patients required hospitalization for the resolution of the episodes and for the diagnostic and therapeutic work-up. Data on psychomotor development before the onset of CSE, full neurological examination and brain magnetic resonance imaging (MRI), ictal and inter-ictal electroencephalography (EEG) record- ings were obtained. The diagnosis of PS was made following the electro-clinical criteria indicated by Panayiotopoulos3 and Car- aballo et al., 4 i.e., (1) at least one afebrile seizure featuring
autonomic manifestations, with or without other ictal clinical manifestations (e.g., eye deviation, motor phenomena), followed by impaired consciousness with secondary generalization; (2) occipital and extra-occipital spikes at the interictal EEG; (3) normal neurological development and (4) unremarkable brain imaging. Once the diagnosis was made, all patients were followed for at least 5 years. The following clinical data were analyzed: (a) age at seizure onset, (b) treatment strategies, (c) duration of treatment, (d) EEG findings at the onset and during follow-up and (e) clinical outcome during and off treatment.
To compare the electro-clinical evolution of patients with CSE, we also recruited 72 age and sex-matched children, aged 2–14 years, with PS but without having shown CSE. All children underwent a careful neurological examination, inter-ictal EEG and neuroimaging. The two groups were compared with regard to the following aspects: no therapy, monotherapy, polytherapy and seizure outcome.
Statistical analysis was conducted using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Comparisons between groups were performed with Student T-test for continuous variables and with X2 test for categorical variables. Statistical significance was defined as a p-value <0.05.
3. Results
3.1. Onset of CSE
Twenty-seven patients had CSE with generalized clonic seizures, while 10 showed focal clonic seizures affecting one side of the body or both sides alternatively.
Ictal EEGs were recorded in 20 patients (54.1%): 12 (32.4%) children showed epileptic discharges in occipital lobes, 4 (10.8%) also in the temporal lobes, while the other 4 patients showed only generalized discharges (see Fig. 1). Cerebrospinal fluid analysis (10 patients) was unremarkable in all cases.
All patients underwent brain MRI at the time of CSE and no abnormalities were observed in any children.
Eleven (29.7%) children required admission to Intensive Care Units for the intensive monitoring and treatment of CSE.
All subjects performed an interictal EEG: most subjects (83.78%) showed occipital spike activity. Twenty-two of these patients have not presented further events of CSE, therefore the interictal EEG led the clinician to the diagnosis of PS. Other 5 (13.51%) patients had fronto-central, multi-focal or temporo- occipital spike-wave foci and only 1 presented generalized abnormalities after resolution of CSE.
A. Verrotti et al. / Seizure 23 (2014) 728–731730
3.2. Treatment of CSE
Eleven out of 37 patients (29.7%) required admission to the Intensive Care Units for the maintenance and/or stabilization of vital functions, to arrest seizure activity and to monitor critically ill patients. All 11 children received one administration of benzo- diazepines as ‘first-line drugs’ for the treatment of the initial CSE; specifically, 5 of them received two consecutive doses of benzodiazepines. Given the failure of this treatment, phenytoin (dose 20 mg/kg) was administered to nine children, while two of them were treated with phenobarbital. None of these seizures evolved in refractory CSE.
CSE of the remaining 26 patients resolved without the need of intensive care. A single administration of benzodiazepines was sufficient to disrupt CSE in 20 patients, while for the remaining 9 children a second dose of benzodiazepines was necessary.
3.3. Follow-up
After resolution of CSE, 14 (37.8%) patients were treated with monotherapy. Valproic acid (VPA) was the most common drug administered in the 8 centers, at a dosage of 22.7 9.8 mg/kg/ day. For 2 children (5.40%) a polytherapy was required. In particular, one patient received carbamazepine (CBZ) and clonaze- pam, while another was treated with the association of CBZ and oxcarbazepine (OXC), without important side effects. One patient
Table 1 Electroclinical features, AED therapy and outcome of seizures in patients (n = 37)
with PS and convulsive status epilepticus (CSE) at the onset versus patients with PS
without CSE (n = 72).
Clinical history
Personal history of seizures, n (%) – 2 (2.77%)
Psychomotor development
Age at Seizure Onset
Generalized abnormalities, n (%) 4 (10.81%) –
Interictal EEG patterns
Generalized abnormalities, n (%) 1 (2.37%) –
Multiple alterationsa, n (%) 5 (13.51%) 8 (11.1%)
Intensive Care Unit Admission 11 (29.72%) –
Outcome
Add-on drugs, n (%) 2 (5.40%) –
Intractable Epilepsy. n (%) – –
Monotherapy, n (%) 4 (10.81%) 1 (1.38%)
Polytherapy, n (%) – –
Follow-up duration,
Not controlled, n (%) – 1 (1.38%)
a Multiple alterations = fronto-central, multi-focal, temporo-occipital.
experienced side effects following the administration of CBZ. There were no reported interactions with the antiepileptic drugs (AEDs) used.
All patients had the first follow-up assessment within 3 months after CSE.
After CSE, considered for all subjects as the first event, 15 patients had at least 2 more seizures with electro-clinical features of PS in the first 2 years of follow-up. For all other patients of the study-group, who showed autonomic symptoms and/or interictal EEG typical of PS immediately after CSE (within 24 h), CSE was considered the only ictal event. The interictal EEGs (i.e.: occipital spike activity) and/or autonomic symptoms typical of PS (i.e.: tonic eye deviation, vomiting, etc.) led to the diagnosis.
Afterward, a strict follow-up was performed for at least 5 years in all children: no patient was lost during follow-up (mean duration 5.6 1.1 years). No patients presented other episodes of CSE. All patients were seizure free at the last follow-up visit.
In all patients (except 2 subjects who showed persistence of intermittent occipital spikes for one year), interictal EEG became normal after around 6 months from the beginning of anticonvul- sant therapy and persisted normal during the whole follow-up period.
At the end of the follow-up, a comparison between the group of patients with and without CSE was performed. No significant differences in any parameters were observed between the two groups.
Table 1 shows the results for the two study groups.
4. Discussion
To our knowledge, there are no prospective studies addressing CSE as a clinical feature of PS. Our study suggests that CSE should be considered as one of the possible presentations of PS. Indeed, Panayiotopoulos considered CSE as a rare event in PS, although brief hemiconvulsions are reported in 40% of children.18,19
Sanders et al. reported a case of a 3-year-old male child with PS who presented a status epilepticus at the onset followed by a cardiorespiratory arrest, requiring cardiopulmonary resuscita- tion.9 However, most of the signs and symptoms reported were autonomic without any description of seizures at the onset of PS. Furthermore, cardio-respiratory arrest was reported in four out of around 1000 cases that recovered completely.13
Caraballo et al.20 reported a case who initially had typical PS but later showed behavioral and neuropsychological impairments, probably in association with continuous spikes and waves recorded on EEG during sleep. Saitoh et al. reported a 10 year- old girl who showed short consciousness alterations 4 years after the onset of typical Panayiotopoulos seizures.21
Michael et al.23 performed a literature review to clarify features of PS and Gastaut syndromes,in particular to assess seizure prognosis and the clinical management of these two forms of idiopathic epilepsies. They considered frequency of clinical seizures, seizure semiology and frequency and location of interictal spikes on EEG22,23 as potential prognostic factors. They found that CSE at the onset has little effect on long-term prognosis. Even after the most severe manifestations, all patients recovered after a few hours of sleep. We believe that the prognosis of patients with PS is good, independently of the type of onset, with or without CSE. At the last follow-up, 33 (89%) out of our patients did not need any anti-epileptic therapy.
The prognosis of a typical PS is considered excellent. Compared to children with intractable epilepsy, those with PS are considered to have a benign focal epilepsy, and they go into remission without treatment with AEDs until adolescence.24 Remission often occurs within one to two years after onset, generally before 12 years of age. Only 5–10% of the subjects may present recurrences of
A. Verrotti et al. / Seizure 23 (2014) 728–731 731
autonomic attacks (even more than 6–10 times), which can be either brief or prolonged, and they are refractory to conventional AEDs therapy.25
In the present study, for 11 children, it was not sufficient to administer benzodiazepines to stop discharge activity and to stabilize vital functions, but it was necessary to administer a ‘second-line drug’ to arrest prolonged seizures. None of these patients experienced a refractory CSE, but they showed a remarkable response to benzodiazepines associated or not to ‘second-line drugs’, with resolution of CSE. The response to therapy was complete, without the development of epilepsy resistant to therapy. Our patients presented a homogeneous prognosis with complete seizure control and epilepsy remission similar to those observed in the group of patients who did not experience CSE. Although our patients were treated in different neuropediatric centers, all of them were followed for a long period of time, allowing a clear evaluation of their long-term prognosis.
In addition, in this study 16 children received chronic AED treatment, in particular 14 were treated with monotherapy and it was necessary to add an AED for two children. We have already said that the prognosis of PS is very good, therefore AED treatment is usually not recommended for patients with a first seizure. However, studies conducted in different centers demonstrated that it would be better to consider treating patients with VPA, CBZ or clobazam after a second or third seizure, according to the length of seizures, the association of mild neurobehavioral disorders and if the parents agree, once informed about chronic AED side effects.26,27 Treatment with AEDs is associated with potential acute and chronic side effects and relevant costs. Furthermore, it is unknown whether AED treatment may effectively suppress epileptic EEG abnormalities or improve cognitive and behavioral functions.28 Thus, the period of treatment should be two to three years after the last seizure; thereafter AEDs are discontinued, without waiting for the disappearance of epileptic EEG spikes. In our study-group, more than 89% of the patients had already stopped treatment at the last follow-up and one patient was reported to have side effects with the administration of CBZ.
In conclusion, the present study demonstrates that CSE can occur at the onset of PS, although it is not associated with a poor prognosis. Over the years, the concept of PS has been expanded, and now includes a wider and larger spectrum of seizures far beyond the occipital manifestations.29 However, many theoretical and practical points, including diagnostic, genetic, and pathophys- iologic issues still remain unsolved for PS and the complete definition of PS is still a challenge. The identification of missing pieces in the PS puzzle will probably require a multidisciplinary prospective and evidence-based approach.
Conflict of interest
None of the authors has any conflict of interest to disclose.
Acknowledgments
We thank Mrs. Rosamund M. Chilman for language revision. We thank also Dr. M. Loredana Marcovecchio for critically reviewing the manuscript.
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